Genetic Variant NM_173812.5:c.1961C>G (chr12-63570797-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_173812.5(DPY19L2):c.1961C>G(p.Pro654Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DPY19L2
NM_173812.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.32

Variant links:

Genes affected

DPY19L2 (HGNC:19414): (dpy-19 like 2) The protein encoded by this gene belongs to the dpy-19 family. It is highly expressed in testis, and is required for sperm head elongation and acrosome formation during spermatogenesis. Mutations in this gene are associated with an infertility disorder, spermatogenic failure type 9 (SPGF9). [provided by RefSeq, Dec 2011]

DPY19L2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPY19L2	NM_173812.5 link	c.1961C>G	p.Pro654Arg	missense_variant	Exon 20 of 22	ENST00000324472.9	NP_776173.3	Q6NUT2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DPY19L2	ENST00000324472.9 link	c.1961C>G	p.Pro654Arg	missense_variant	Exon 20 of 22	1	NM_173812.5	ENSP00000315988.4	Q6NUT2-1
DPY19L2	ENST00000413230.6 link	n.707C>G		non_coding_transcript_exon_variant	Exon 4 of 6	2
DPY19L2	ENST00000439061.6 link	n.*247C>G		non_coding_transcript_exon_variant	Exon 9 of 11	5		ENSP00000437474.1	H0YF77
DPY19L2	ENST00000439061.6 link	n.*247C>G		3_prime_UTR_variant	Exon 9 of 11	5		ENSP00000437474.1	H0YF77

Frequencies

GnomAD3 genomes

AF:

0.0000660

AC:

AN:

151464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250864

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135580

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460948

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726794

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000660

AC:

AN:

151464

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73914

show subpopulations

Gnomad4 AFR

AF:

0.000219

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1961C>G (p.P654R) alteration is located in exon 20 (coding exon 20) of the DPY19L2 gene. This alteration results from a C to G substitution at nucleotide position 1961, causing the proline (P) at amino acid position 654 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

Eigen

Benign

0.17

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.33

Sift

Benign

0.091

Sift4G

Benign

0.11

Polyphen

0.49

Vest4

0.93

MVP

0.56

MPC

0.68

ClinPred

0.53

GERP RS

3.3

Varity_R

0.49

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over